








key: cord-345275-h0hvaxgx
authors: Sun, Mengyao; Xu, Yinghui; He, Hua; Zhang, Li; Wang, Xu; Qiu, Qing; Sun, Chao; Guo, Ye; Qiu, Shi; Ma, Kewei
title: Potential effective treatment for COVID-19: systematic review and meta-analysis of the severe infectious disease with convalescent plasma therapy
date: 2020-07-04
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.06.107
sha: 
doc_id: 345275
cord_uid: h0hvaxgx

Abstract Background Convalescent plasma (CP) has been used successfully to treat many types of infectious diseases, and it has shown initial effects in the treatment of the emerging 2019 coronavirus disease (COVID-19). However, its curative effect and feasibility have yet to be confirmed by formal evaluation and well-designed clinical trials. To explore the effectiveness of treatment and predict the potential effect of CP for COVID-19, studies of different types of infectious diseases treated with CP were included in this systematic review and meta-analysis. Methods Related studies were obtained from databases and screened based on the inclusion criteria. The data quality was assessed, and the data were extracted and pooled for analysis. Results We included 40 studies on CP treatment for infectious diseases We found that CP treatment could reduce the risk of mortality with a low incidence of adverse events, promote the production of antibodies, show the decline in viral load, and shorten the disease course. A meta-analysis of 15 controlled studies showed that there was a significantly lower mortality rate in the group treated with CP (pooled OR = 0.32, 95% CI: 0.19-0.52, P < 0.001, I2 = 54%) than in the control groups. Studies were mostly of low or very low quality with a moderate or high risk of bias. The sources of clinical and methodological heterogeneity were identified. The exclusion of heterogeneity indicated that the results were stable. Conclusions CP therapy has some curative effect and is well tolerated to treat infectious diseases. It is a potentially effective treatment for COVID-19.

3 lead to death in severe cases [1] . The epidemic causing more than 2 million infections and 140 thousand deaths so far has spread quickly worldwide since December 12, 2019 , and the number of infections is gradually increasing throughout the world. To date, there are no approved specific antiviral agents for COVID -19, convalescent plasma (CP) therapy has shown some effect and is strongly expected to be used to treat COVID -19. The China National Biotech Group reported on February 13, 2019, that it had detected high titers of virus-neutralizing antibodies as a result of CP. More than 10 patients with severe disease had significantly improved clinical outcomes 12-24 hours after CP transfusion, which is meaningful for the human race in the fight against COVID -19.

CP therapy is a form of passive immunisation in which antibody-rich blood is collected from recovered patients and then processed to transfuse into other patients.

Neutralizing antibody is the key effective factor: it blocks the entry of the virus into a cell by binding to the virus and regulates the immun e system to mediate the phagocytosis of immune cells and remove the virus. CP therapy has been effective for treating diphtheria and tetanus since the late 19th century, but the earliest complete record dates back to the outbreak of the Spanish influenza pandemic in 1918. Later, CP was used to treat Ebola, SARS, MERS, pandemic influenza, and other unexpected major infectious diseases; additionally, some progress has been made in related research [2 -4] . Two systematic reviews on respiratory infection revealed a significant reduction in the pool odds of mortality following CP therapy [5, 6] . These experiences raise the hypothesis that use of CP transfusion could be beneficial in patients infected with SARS -CoV-2. Food and Drug Adminiastrtion (FDA) has approved use of CP to treat severe COVID-19 patients. [7] However, its curative effect and feasibility have yet to be confirmed in a large clinical trial, and further study is required to develop specific treatment criteria. To predict the potential effect of CP in COVID-19, we conducted a systematic review and meta-analysis of different types of infectious diseases treated with CP and further investigated the key points of CP treatment. 

Literature collection According to the literature retrieval strategies recommended by the Cochrane Collaboration, databases such as PubMed, Web of Science, Embase, and the Cochrane Library were comprehensively searched for journal papers published from the time the databases were created to March 30, 2020 with the keywords "convalescent plasma", "SARS", "MERS", "Ebola", "H1N1", "H5N1", "H7N9" and "influenza". Additionally, the references of selected studies were searched to identify other eligible studies.

The included studies were as follows: (i) The population of interest was human subjects of any age or sex who were diagnosed with SARS, MERS, Ebola, influenza, and other epidemic diseases with a laboratory-confirmed or suspected viral etiology. (ii) Study designs included randomised controlled trials (RCTs), nonrandomised single-arm intervention studies, prospective and retrospective cohort studies, case reports and case series, and studies with no control group. (iii) The intervention measure was convalescent blood products containing CP (iiii) reporting at least one outcome of interest (mortality, symptom duration, hospital length of stay, antibody levels, viral load, adverse events and other specific outcomes of CP therapy). We excluded (i) reviews and guiding documents, including clinical guidelines and expert consensus, (ii) animal or in vitro cell studies, (iii) studies for which the full text was not available, (iiii) and studies with insufficient data on clinical information. Two investigators independently screened the titles and abstracts of the retrieved citations and then assessed the full-text manuscripts that were considered potentially eligible.

Data extraction and quality assessment

The following information was extracted from the collected literature: article title, first author's name, year of publication, study methods, number of patients, types of infectious disease, details of treatment and clinical outcomes. The Cochrane bias risk J o u r n a l P r e -p r o o f 5 assessment tool version 5.1 was used to assess the quality of ran domised or prospective controlled studies [8] . The Newcastle-Ottawa Scale (NOS) was used for other clinical observational studies [9] . The risk of bias in the included studies was independently assessed by two investigators. Differences were solved by discussion or through consultation with the senior investigator.

Meta-analysis was conducted using Review Manager 5.3 software. The Mantel-Haenszel method was used to determine the odds ratio (OR) and 95% confidence interval (95% CI). We considered P ≤ 0.05 to be statistically significant. The assessment of between study statistical heterogeneity was based on the I 2 statistic. A high value for I 2 (＞50%) indicates heterogeneity, in which case the random effects model was used, and subgroup analysis was performed according to the factors that may be the source of the heterogeneity.

In contrast, for I 2 ≤50%, the fixed effect model was recommended. The analysis of sensitivity and the source of the heterogeneity were evaluated by (1) changing the analysis model and (2) screening the included studies to assess the impact of each study on the outcomes.

According to the search criteria, a total of 3524 studies were initially selected, among which 40 studies were included. The screening process was shown in Figure 1 [17] [18] [19] [20] , 4 studies reported outcomes for 29 patients with avian influenza A (H5N1) [21] [22] [23] [24] , and 15 studies reported outcomes for 1803 patients with Spanish influenza A (H1N1) [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] . Clinical outcomes of one patient with avian influenza A (H7N9) were reported [40] . One study including 87 patients with diverse severe influenza was found [41] . For infection with J o u r n a l P r e -p r o o f 6 Ebola virus, 6 studies reporting outcomes for 583 patients were included [42] [43] [44] [45] [46] [47] . Four studies of 31 patients infected with SARS-CoV-2 was included [48] [49] [50] . There were 2 nonrandomised prospective studies, 1 randomised prospective study, 12 nonrandomised intervention and cohort studies with control groups, and 25 case series and case reports with no control group. Supplementary Table 1 

The risks of bias of the 3 prospective controlled studies were considered to be moderate according to the Cochrane Collaboration tool, and all of them were at a high risk of bias in allocation concealment and blinding (Supplementary Table 2 ). Supplementary Table 3 summarizes the results of the 37 observational studies for which the NOS was used for quality assessment. Most of the studies had a moderate to high risk of bias, among which the expected absence of random and blinded intervention was the common caveat, and 25 studies were at extremely high risk of bias due to the lack of a control group .

A retrospective controlled study on SARS-CoV showed no deaths in 19 patients who received CP therapy, and there was a statistically significant difference in the case fatality ratio (CFR) compared with the control group (0% vs 23.8% 95% CI, 6 to 42 P=0.049) [10] .

Cheng et al. reported a CFR of 12.5% in 80 patients who received CP therapy in Hong

Kong, but the SARS-related CFR in Hong Kong was 17% during the same period [11] . No deaths treated with CP were reported in any of the 4 studies that enrolled fewer than 5 patients infected with SARS [12] [13] [14] [15] . In the retrospective controlled study conducted b y Hung et al. on patients with influenza A (H1N1) pdm09 who underwent CP therapy via an 7 antibody titer higher than 1:160, the multivariate analysis showed that the intervention group had a significantly lower CFR than the control group (20% vs 54.8%, OR=0.20; 95% CI, 6 to 69; P=0.011) [17] . In addition, in the 3 small case series or case reports on CP therapy for patients with influenza A (H1N1) pdm09, only 1 death was reported by Sang et al. [18] [19] [20] . However, there was no significant difference (95% CI, 52 to 89; P=0.11) between the 2 groups in a case series of patients with avian influenza A (H5N1); 2 of 26 patients received CP therapy, and the CFRs of the intervention group and control group were 0% and 70%, respectively [22] . The absolute reduction of CFR in the CP group was observed in 3 nonrandomised controlled studies on Spanish influenza A (H1N1) (6.7% vs 28.3%, P=0.008, 95% CI, 11 to 32; 6.5% vs 25%, P<0.001, 95% CI, 8 to 30; 4.0% vs 30%, P<0.001, 95% CI, 21 to 31) [25, 26, 33, 34] . In a randomised, prospective, phase II clinical study on CP therapy for severe influenza conducted by John et al, CRF was 2% (1/49) in the treatment group, which was lower than 10% (5/49) in the control group, but there was no statistically significant difference between them (P=0.093) [41] . A study of CP therapy for patients with Ebola virus showed that the risk of death was 31% in the CP group and 38% in the control group from day 3 to day 16 after diagnosis (RD: -7%; 95% CI: -18 to -4), and the difference was reduced after adjustment for age and cycle-threshold value (RD: -3%: 95% CI: -13 to 8) [42] . Another controlled study on Ebola virus showed that the CFR was 28% (12/43) in the CP group and 44% (11/25) in the control group. However, there was no significant difference between the intervention and control groups in these 2 studies [43] . Mupapa et al. reported 1 death (CFR: 12.5%) in 8 patients with Ebola hemorrhagic fever after treatment with convalescent whole blood, while the overall CFR of this epidemic was 80% [44] .No deaths were reported in patients infected with SARS-CoV-2 using CP therapy. (Table 1-2) . 

Viral loads are highly correlated with disease severity and progression [52] .The

indicators of viral load were tested before and after CP therapy in several studies. Yeh et al. found that the viral loads decreased from 495×103, 76×103 or 650×103 copies /ml to 0 or 1 copy/mL in 3 patients with SARS-CoV on day 1 after CP transfusion [14] . Hung et al. recorded that the viral loads of patients with influenza A (H1N1) pdm09 were significantly lower in the CP therapy group than in the control group on days 3, 5, and 7 after admission to the ICU (P=0.001, P=0.02 and P=0.04) [17] . The virus was not detected in the serum of one patient with avian influenza A (H5N1) on day 7 and day 16 after CP therapy [21] . The viral load was reduced by approximately 12 times (from 1 .68×105 to 1.42×104 copies) in another H5N1-infected patient within 8 hours after CP therapy, and no virus was detected within 32 hours [24] . Wu et al. reported that no avian influenza A (H7N9) virus was detected in an infected patient on day 4 after CP therapy. However, in randomised controlled trials of CP therapy for multiple severe influenzas, there was no significant difference between the intervention group and the control group regarding the time when no virus was detected [40] . In a controlled study of Ebola, the PCR cycle threshold increased by 3.5 cycles on day 1 after CP transfusion (the Ct value was inversely J o u r n a l P r e -p r o o f 9 proportional to the viral load) [42] . Another study of convalescent whole blood treatment for Ebola virus showed that there was a significant difference between the virus quantification at admission and that within the first 24 hours (P<0.01). In the intervention group, the mean Ct value was 23.37±5.0 at admission compared with 29.99±5.9 at 24 hours after blood transfusion. In the control group, the mean Ct value was 31.97±8.4 at admission vs 31.25±7.5 at 24 hours after admission [43] . Kraft × 105 copies/ml to 180 copies/ml 5 days after the completion of CP transfusion and RT-PCR was negative on day 10 after the completion of CP transfusion [49] . A case series of 5 COVID patients was reported by Shen et al that Ct value increased within 1 day after transfusion and became negative on posttransfusion day 1-3 in 3 patients, 2 became negative on day 12 after the transfusion.They also found that SARS-CoV-2 was still detectable in all 5 patents even though antiviral treatment had been given for at least 10 days, however, viral load decreased and became undetectable soon after CP treatment, which highlight the possibility that CP have contributed to the clearance of the virus. [50] The case reports from Korea recorded the Ct value of 2 patients with SARS-CoV-2 before and after CP therapy. In 1 patient, Ct value was changed from 24.98 to 33.96 on day 9 after CP infusion, and the viral was negative after on day 15 after CP infusion. Similarly, Ct value of another patient changed from 20.51 before CP infusion to 36.33 on day 3 after plasma infusion [51] . Based on the above results, it can be concluded that CP therapy can reduce the viral load of infectious diseases to some extent (Table 1- Some of the included studies described the level of antibodies after CP therapy but provided no data on the comparison between the intervention group and the control group.

Yeh et al. reported that SARS-CoV IgG and IGM antibodies in patients increased in a timedependent manner and reached a peak on day 3 to day 5 after CP therapy [14] . According to the test of antibody levels of a patient with avian influenza A (H5N1) from Hong Kong who received CP therapy, specific antibodies to H5N1 appeared between the 7th and 16th days of treatment with CP [21] . Zhou et al. also reported that the specific antibodies rose from negative to a titer of 1:40-1:80 within 5 days after CP therapy in one H5N1-infected patient [24] . One patient with avian influenza A (H7N9) was found to have a neutralizing antibody titer of more than 1:80 at discharge on day 16 after CP therapy [40] . A case report of an Ebola-infected patient found that IgM antibodies increased almost linearly after CP 

According to a study of CP therapy for SARS-CoV-infected patients, patients received J o u r n a l P r e -p r o o f 11 CP in the initial 14 days from diagnosis had a better outcome than those received CP after day 14 from diagnosis(58.3% vs 15.6%; P<0.001). The CFR in the two groups was 6.3% and 21.9%, respectively (P=0.08) [11] . Another controlled study on SARS-CoV also showed poor clinical responses in patients who received CP therapy after day 16 [10] . Four studies on Spanish influenza A (H1N1) showed that early treatment with CP could significantly improve the prognosis, and 2 of the studies provided data showing that patients who received the therapy before day 4 had a lower risk of mortality than those who received the therapy after day 4 (32% vs 60%; 95% CI: 2%-53%; P=0.85 and 14% vs 40%; 95% CI: -2%-72%; P=0.86) [32] [33] [34] [35] [36] [37] . In a study of 16 patients with Spanish influenza A (H1N1) who died after CP therapy, the transfusion was provided quite late in 13 patients [39] . Based on the above results, it can be concluded that the early use of CP may improve the outcomes of severe infectious diseases (Table. 1 -2).

A study involving patients infected with SARS-CoV showed that 74% of patients who received CP were discharged by day 22, compared with 19% in the control group (p=0.001) [10] . Zhou et al. reported one case of SARS-CoV-infected patient recovered within 21 days having a shorter disease course [16] . In a study of Ebola virus, the average recovery time was 10.6±3.4 days for patients treated with convalescent whole blood compared with 12.23±4.8 days for the control group [43] . Chan et al. reported that the average length of hospital stay after CP transfusion was shorter than that in the control group in 3 patients infected with influenza A (H1N1) pdm09 (36.6 days vs 60 days; P=0.23) [20] . According to the included studies of patients with severe cases and influenza, there were fewer days in the hospital after randomization (median 6 days vs. 11 days, p= 0.13) [41] . To some degree, CP therapy for infectious diseases can reduce the length of hospital stay, shorten the course of disease and contribute to the recovery of patients (Table 1 -2).

No serious adverse events (SAE) related to CP therapy were reported in most of the included studies. According to some relevant stud ies on Spanish influenza A (H1N1), the J o u r n a l P r e -p r o o f 12 most common CP-related adverse events were chills and a temporary increase in temperature, which mainly occurs 30-120 minutes after blood transfusion. Gould et al. found that the occurrence of jaundice and phlebitis might be associated with blood transfusion [25] [26] [27] [31] [32] [33] [34] [35] [36] [37] . Two studies on Spanish influenza showed that transfusion might aggravate serious symptoms or hasten death in terminally ill patients [26, 35] . Kraft et al. reported that CP transfusion was associated with worsening shortness of breath and increasing oxygen requirements in 1 patient with Ebola virus [45] . A case report of one Ebola-infected patient had ARDS possibly caused by transfusion -related acute lung injury, which was managed without mechanical ventilation [46] . A study of severe influenza reported that the incidence of SAE was 20% in 42 patients after CP therapy, including ARDS and stroke [41] . In general, CP infusion is well tolerated, and it is rare to observe serious CP-related adverse events. Attention should be paid to terminally patients for exacerbation of the symptoms or disease (Table 1 -2).

According to the results of the pooled analysis of different types of infectious diseases, CP therapy is effective for reducing the mortality rate and had a significant effect on adjusting the immune system and decreasing the viral load.The synthesis of the length of hospital stay indicates that CP therapy can shorten the course of disease and contribute to patient recovery. The low incidence of serious adverse events, which are mostly controllable, has been shown during and after CP infusion. SARS-CoV immunoglobulin was prepared successfully using CP in 2004, and it has been approved by the Chinese Food and Drug Administration as an emergency rescue drug for the treatment of SARS -CoV.

World Health Organization (WHO) has identified CP as a treatment for Middle East respiratory syndrome coronavirus (MERS-CoV), and the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) has recommended CP infusion as a potential treatment for reducing the clinical symptoms of MERS -CoV infection [53] .

In response to SARS-CoV-2 outbreak, the administration of CP to severe patients was J o u r n a l P r e -p r o o f 13 included in Chinese guidelines for the treatment of COVID-19 [54] . FDA also provided emergency access to for patients with serious or immediately life threatening COVID-19 infections [7] .

The practice of treating severe infectious diseases with blood products collected from recovered patients reveals the importance of antibodies. The curative effect of CP therapy is attributed to the protective antibodies that block the virus durably and efficiently. It was reported that the immune response is associated with the neutralizing activity of antibodies.

After infusion with a 1:80 CP titer in a plaque-reduction neutralization test (PRNT), MERS-infected patients showed a significant immune response, but the plasma with a PRNT titer of 1:40 had no similar response [55] . The patients who had no significant improvement in survival after CP infusion possibly had a lower titer of neutralizing antibodies. Therefore, to make the CP more effective, the effective neutralizing antibody titers of CP need to be further explored, and the level of neutralizing antibodies in donor plasma should be determined before transfusion.

Whether the antibodies in CP are definitely beneficial for treatment is a question. In addition to the complexity of blood products that present risks such as allergic reactions and pathogen transmission, the antibodies probably have a impact on disease severity [56] .

The evidence from animal models of SARS-CoV suggests that the role of antibodies was related to the developement of more severe acute lung injury [57] . Studies on the pathogenesis of SARS-CoV-2 have shown that as the virus attacks the human body, it can trigger a specific immune response; subsequently, a variety of cytokines are produced abundantly. While killing pathogens, cytokines also damage normal tissues and organs in an effect called a cytokine storm. As reported in the clinical data on SARS-CoV-2 infections in China, cytokine storms are observed in patients with severe disease [58] .

There are neutralizing antibodies in CP that prevent the virus from attacking the human body, and nonneutralizing antibodies mainly mediate the virus's entry into macrophages, but when the virus multiplies rapidly in the macrophages, the macroph ages can release excessive pro-inflammatory factors that aggravate the cytokine storm [59, 60] . This may be the explanation that CP therapy worsens the symptoms and hastens the death of J o u r n a l P r e -p r o o f 14 terminally patients with Spanish influenza A (H1N1), as well as a potential factor that causes CP-related ARDS in Ebola-infected patients. Therefore, we need to be alert for the cytokine storm when applying CP therapy. Avoiding the cytokine storm and the reasonable application of CP are the keys for the treatment.

The collection and treatment of CP should be performed at the right time to ensure effective antibody titers and boost the patient immune response in the most timely manner.

Various studies have shown that early treatment with CP resulted in better clinical outcomes than later intervention. There is a 10-day incubation period before the antigen stimulates the primary immune response. Later, low-affinity IgM and then low-affinity IgG antibodies will be produced and will peak on day 21. High-affinity IgG antibodies can be produced quickly (in 3-5 days) only as a secondary response [53] . Therefore, CP should be given early in the course of the disease, when IgG antibodies have not yet been produced in the body. At this time, the passive infusion of high-level and high-affinity IgG can improve the humoral immune response, reduce the repeated stimulation of killer T cells in the immune system, avoid cytokine storms, and prevent the disease from worsening or progressing to a critical stage.

In China, the collection of blood products is highly regulated. In addition to conventional pathogens and the biological indicator, more than 30 types of pathogens from the respiratory, digestive and urogenital systems were screened in plasma of donors who have recovered from COVID-19. Furthermore, the process of viral inactivation of plasma is required to ensure the safety of CP [53] . CP collection is an established method in which only plasma is collected, and blood cells are transfused back into the donor. Plasma donation has little effect on cured patients, and plasma transfusion is a routine medical procedure. Therefore, it is safe and feasible to carry out CP therapy. 

The present study had several limitations. The lack of high -quality studies was a deficiency of our analysis, and the majority of the included studies were at a moderate to high risk of bias, some of which lacked a control group. The absence of blind intervention in controlled studies promotes this situation. Given the limits of database searches and manual retrieval, we cannot be certain that all of the literatures on CP therapy were included, especially reports on Spanish influenza from 1918 to 1920. Since the record methods of various studies are not unified, some clinical outcomes cannot be analyzed quantitatively. The treatment for infectious diseases is diverse and individualized, and we did not exclude factors that might influence the clinical outcomes, which leads to interference with the evaluation of CP therapy.

According to our analysis and prediction, CP has some curative effect and is a safe method to treat infectious diseases early after symptom onset. CP is a potentially effective treatment and can serve as a promising rescue option for severe COVID -19 cases. Welldesigned clinical trials and further investigation for CP therapy are warranted in the future. 

The authors declare that they have no confilict of interest. 

The study does not require ethical approval because the meta-analysis is based on published research and the original data are anonymous. No adverse events were observed with CP In 1 patnent, the fever subsided, and oxygen demand decreased after 1 day of CP transfusion. CRP and IL-6decreased to normal range on 7day after CP infusion.

In another patient, leukocytosis and lymphopenia were immediately recovered after CP infusion.The level of CRP and IL-6 also recovered to the normal range

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Not applicable.

In 4 (57%) of 7 transfusion recipients tested, EBO IgG or IgM antibodies were present before transfusion (only 2 of them had both IgG and IgM antibodies). After transfusion, IgG and IgM antibodies were detected in 7 (87.5%) of the 8 blood 

